脂質液胞，或稱為微脂體(liposomes)，由於其低毒性與高生物相容性，在藥物傳遞中被廣泛用作藥物載體。溫度對微脂體的結構特性有著關鍵作用：在相變溫度(Tm)以上，脂質膜表現出液態無序(liquid-disordered, Lα)相的液態性質，而在Tm以下，則表現出凝膠相(gel, Lβ)的固態性質。為了確保藥物釋放的有效性，關鍵即相態的控制，因此雙層膜的Tm顯得尤為重要。本研究中，我們採用多尺度分子動力學(molecular dynamics, MD)模擬來研究膽固醇和單棕櫚醯磷脂醯膽鹼(1-palmitoyl-sn-glycero-3-phosphocholine, MPPC)如何影響二棕櫚醯磷脂醯膽鹼(1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine, DPPC)雙層膜的相行為。在低溫的粗粒化(coarse-grained, CG)模擬中，我們發現MPPC和膽固醇在膜中的分佈並不均勻。MPPC聚集的區域傾向於形成Lα相，而含有較多膽固醇的區域主要處於Lβ相，這導致了雙成分(DPPC + MPPC)與三成分(DPPC + MPPC + CHOL)系統中的相共存。由於觀察到膜內不同區域的組成差異，我們接著使用全原子(united-atom, UA)模型，針對不同組成進行小尺度模擬。結果顯示MPPC的加入在脂質雙層膜中引發了無序效應，在低溫下導致指叉結構的形成。此外MPPC的加入能夠降低脂質膜的Tm。另一方面，膽固醇在Lα相中誘發有序效應，而在Lβ相中引發無序效應。當膜中膽固醇莫耳分率達到0.3後，系統相變趨勢將會消失，導致液態有序(liquid-ordered, Lo)相的出現。這些模擬結果皆與實驗結果一致，為設計具有熱響應性的靶向藥物輸送微脂體提供了微觀上的見解。

Lipid vesicles, or liposomes, are widely used as drug carriers in pharmaceutical applications due to their low toxicity and high biocompatibility. Temperature plays a crucial role in the structural properties of a liposome: the liposomal bilayer exhibits liquid-like properties in the liquid-disordered (Lα) phase above the main phase transition temperature (Tm), and solid-like properties in the gel (Lβ) phase below Tm. Modulating the membrane phase is vital for effective drug release, making the control of Tm in bilayer systems essential. In this work, we employed multiscale molecular dynamics (MD) simulations to investigate how cholesterol and the lysolipid additive MPPC influence the phase behavior of DPPC bilayers. Coarse-grained (CG) simulations at low temperatures revealed the nonuniform distribution of MPPC and cholesterol in the membrane. We observed that regions where MPPC aggregated tended to form the Lα phase, while regions with a higher proportion of cholesterol are predominantly in the Lβ phase. This led to phase coexistence in both the binary (DPPC + MPPC) and ternary (DPPC + MPPC + CHOL) systems. Furthermore, due to compositional differences in various membrane regions, we applied an united-atom (UA) model to perform small-scale simulations under different compositions. The results showed that the addition of MPPC induced a "disordering effect" in the lipid bilayer, causing the formation of interdigitated structures at temperatures below Tm. The incorporation of MPPC can also lower the Tm of the lipid bilayer. On the other hand, cholesterol exerted an "ordering effect" in the Lα phase and a "disordering effect" in the Lβ phase of the lipid membrane. When the molar ratio of cholesterol exceeded 0.3, the Tm of systems disappeared, leading to the emergence of the Lo phase. These simulation results are consistent with experimental findings and provide molecular insights into the design of thermo-responsive liposomes for targeted drug delivery.

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